Abstract T MP114: PPARγ in Endothelial Cells Plays an Essential Role in Protecting Against Vascular Aging: Role of Oxidative Stress and Rho Kinase

Abstract

Although aging is the greatest risk factor for vascular disease and stroke, relatively little is known regarding mechanisms that regulate vascular aging. Endothelial dysfunction - a key element of carotid artery and cerebrovascular disease - progresses with age, greatly increasing the risk for ischemic stroke and cognitive impairment. The nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) is a ligand-activated transcription factor that may exert diverse effects depending on the cell type. Because little is known regarding the role of PPARγ in vascular aging, we used transgenic mice expressing a dominant negative mutation in human PPARγ (V290M) under control of the endothelial-specific vascular cadherin promoter (designated E-V290M) to examine the hypothesis that cell-specific interference with PPARγ would promote age-induced vascular dysfunction. Responses of carotid arteries from adult (11-12 mo) and old (24±1 mo) E-V290M mice and non-transgenic littermates were examined in vitro. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of arteries from adult control and E-V290M mice as well as old control mice. In contrast, responses to acetylcholine in arteries from old E-V290M mice were reduced by more than 50% in old E-V290M mice (P<0.01). Endothelial function in old E-V290M mice was not altered by indomethacin but was restored to normal by tempol (a superoxide scavenger) or VAS-2870 (an inhibitor of NADPH oxidase). Reactive oxygen species can activate Rho kinase (a potential mediator of vascular disease) and inhibition of Rho kinase with Y-27632 restored endothelial function to normal in old E-V290M mice. Relaxation of arteries to nitroprusside, which acts directly on vascular muscle, was similar in all groups. These findings provide the first evidence that age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARγ through mechanisms involving oxidative stress and Rho kinase. This novel role for endothelial PPARγ has implications for understanding vascular pathophysiology as well as therapeutic approaches for age-induced large and small vessel disease.